Asthma and other respiratory diseases have long been treated by the inhalation of appropriate medicament. For many years a widely used and convenient choice of treatment has been the inhalation of medicament from an aerosol created by a pressurized metered dose inhaler (pMDI). Formulations used in pMDIs often comprise particles of medicament suspended in liquefied propellant(s), e.g. CFC propellant(s) and more recently non-CFC propellant(s), such as 1,1,1,2-tetrafluoroethane (HFA134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HFA227).
The consistency/uniformity of the metered dose delivered from a suspension-based pMDI may be compromised in a number of ways. In particular there is generally a difference between the specific gravity of the solid medicament to be dispensed and the liquid component of the aerosol formulation (for example propellant or propellant mixture or mixture of propellant(s) and, if used, liquid excipient(s)). This means that with time, the two components (solid and liquid) tend to separate with the more dense component(s) settling downwardly (sedimenting) and the less dense component(s) rising upwardly (creaming). In a number of medicinal aerosols, the medicament has a higher specific gravity (density) than that of the liquid component of the formulation (e.g. propellant(s)). This often holds true for formulations based on HFA134a. In such formulations the particles of medicament tend to sediment. In other formulations, where the medicament has a lower specific gravity than that of the liquid component of the formulation, the medicament particles tend to cream. The tendency of particles of a particular medicament to sediment or cream, as the case may be, may be accentuated by flocculation of the suspended medicament particles, whereby the flocculation of a suspension can increase the effective particle size from 10 microns or less to well over 1 mm due to the formation of large flocs. This holds particularly true when using HFA 134a and/or HFA 227, because suspensions of many drugs in formulations containing these propellants generally flocculate more coarsely and/or more rapidly than in formulations with CFC propellants.
In the majority of commercial pMDI devices, the metered dose to be administered is filled into the metering chamber of its metered dose valve just after releasing the device after actuation of the previous dose. Since a patient may use the pMDI device once or twice a day or only when needed, the next metered dose to be administered may be retained in the metering chamber for 12 hours, 24 hours or longer. Depending on the particular sedimentation or creaming behavior of the medicinal suspension formulation and/or the orientation of the pMDI device during such periods of non-use, it has been observed that there is a general tendency towards an undesired decrease in the concentration of suspended medicament within the metered dose retained in the metering chamber. Moreover, a tendency towards a loss of dose is generally observed due to sedimentation or creaming (as the case may be) of medicament out of the metering chamber generally back to the formulation chamber, despite the fact such pMDI devices typically include a tortuous flow path and/or a pre-metering chamber between the formulation chamber of the device and the metering chamber of the valve. Even if the amount of medicament loss for a metered dose retained in the metering chamber is relatively small, each such loss over the lifetime of pMDI device may collectively lead to an undesirable, ever-increasing rise in the overall concentration of medicament suspended in the formulation.
Some pMDI devices do not include such dose-retaining, metered dose valves, but rather include herein-called “empty-fill” metered dose valves. Here the valve is designed such that there is very open access to the metering chamber (for example large through-openings to the interior of the valve (e.g. to the pre-metering chamber or to the metering chamber)), so that the metering chamber can be “easily emptied” of formulation and “easily filled” with a fresh metered dose of suspension formulation. Examples of such empty-fill type metered dose valves include commercial valves marketed under the trade designations EasiFill BK361 (from Bespak, Bergen Way, King's Lynn, Norfolk, PE30 2JJ, UK) and DF30 ACT (from Valois SAS, Pharmaceutical Division, Route des Falaises, 27100 le Vaudreuil, France). Other metered dose valves for pMDIs, such as those disclosed and described in U.S. Pat. No. 5,772,085, operate under a shuttle principle, wherein the metering chamber is brought into the formulation chamber so that aerosol formulation can enter the metering chamber and subsequently moved out of the formulation chamber, sealed off and brought into communication with an outlet allowing the metered dose to pass to the patient. Such valves typically do not suffer loss of dose as described above in conjunction with dose-retaining-type valves, since the metering chamber is typically filled with the metered dose to-be-administered just prior to release (assuming that the user has properly used the pMDI device). Nonetheless dose consistency can still be an issue, in particular with suspension formulations having tendencies towards rapid sedimentation or creaming. Moreover although users of suspension aerosols are always instructed to shake (or agitate) a pMDI device immediately prior to use, even a short delay between shaking and actuation of the device may be sufficient to allow some sedimentation or creaming (as the case may be) to occur into or out of the metering chamber due to the open design of such valves, resulting in an undesired change in dose and hence the device dispensing and the user receiving, a dose containing an elevated or a reduced amount of the medicament, respectively.